Anticancer Development Research Articles

Structure and Biosynthetic Gene Cluster of Sulfated Capsular Polysaccharide from the Marine Bacterium Vibrio sp. KMM 8419

Vibrio sp. KMM 8419 (=CB1-14) is a Gram-negative bacterium isolated from a food-net mucus sample of marine polychaete Chaetopterus cautus collected in the Sea of Japan. Here, we report the structure and biosynthetic gene cluster of the capsular polysaccharide (CPS) from strain KMM 8419. The CPS was isolated and studied by one- and two-dimensional 1H and 13C nuclear magnetic resonance (NMR) spectroscopy. The molecular weight of the CPS was about 254 kDa. The CPS consisted of disaccharide repeating units of D-glucose and sulfated and acetylated L-rhamnose established as →2)-α-L-Rhap3S4Ac-(1→6)-α-D-Glcp-(1→. To identify the genes responsible for CPS biosynthesis, whole-genome sequencing of KMM 8419 was carried out. Based on the genome annotations together with the Interproscan, UniProt and AntiSMASH results, a CPS-related gene cluster of 80 genes was found on chromosome 1. This cluster contained sets of genes encoding for the nucleotide sugar biosynthesis (UDP-Glc and dTDP-Rha), assembly (glycosyltransferases (GT)), transport (ABC transporter) and sulfation (PAPS biosynthesis and sulfotransferases) of the sulfated CPS. A hypothetical model for the assembly and transportation of the sulfated CPS was also proposed. In addition, this locus included genes for O-antigen biosynthesis. Further studies of biological activity, the structure–activity relationship in the new sulfated polysaccharide and its biosynthesis are necessary for the development of potent anticancer agents or drug delivery systems.

Exploring 5-Nitro-N-phenyl-3-(phenylamino)-1H-indazole-1-carboxamide (5-NPIC) Derivatives as Anticancer Agents: Synthesis, Docking and Molecular Dynamics Insights

The synthesis and characterization of a series of 5-nitro-[Formula: see text]-phenyl-3-(phenylamino)-1[Formula: see text]-indazole-1-carboxamide 5-NPIC derivatives (5a– 5v) have been reported as anticancer agents in this study. These derivatives were synthesized by reacting 3-chloro-5-nitro-[Formula: see text]-phenyl-1[Formula: see text]-indazole-1-carboxamide (4) with a variety of aniline derivatives in isopropanol. FT-IR, 1H-NMR, 13C-NMR and mass spectral methods were employed to confirm the structures of analogues (5a– 5v). The anticancer activity evaluation of compounds 5a– 5v revealed that 3-((3-methoxyphenyl) amino)-5-nitro-[Formula: see text]-phenyl-1[Formula: see text]-indazole-1-carboxamide (5j) exhibited good efficacy. The stability of ligand–protein complexes was systematically evaluated using molecular dynamics simulations (MDS), which demonstrated a consistent and robust binding of the most potent compound within the binding sites of target proteins. The results confirmed the anticancer activity, which was further substantiated by comprehensive molecular docking analyses that revealed complex interactions involving hydrophobic contacts, electrostatic forces and hydrogen bonds. Our results would collectively provide invaluable insights into the intricate molecular structure and dynamics of receptor target sites, thereby establishing a solid foundation for the development of novel and potent anticancer agents with optimistic pharmaceutical implications in near future.

Biological Activities and Chemical Contents of Edible Hohenbuehelia petaloides (Bull.) Schulzer.

Mushrooms are a good diet with high protein and polyunsaturated fatty acid contents in health, food, and industry from past to present. Mushrooms have attracted a lot of attention in terms of the bioavailability of natural products. Hohenbuehelia petaloides, a member of the Pleuroteceae family, is an edible wood fungus that grows naturally on the trunks of old and decayed trees. In this study, the cytotoxic activities of hexane, methanol, and water extracts of H. petaloides against various cancer cell lines A549, MCF-7, PC-3, and HT-29 were investigated with the 3-(4,5-dimethylthiazol-2-yl)-2,5-dipenyltetrazolium bromide (MTT) assay. In addition, the apoptotic, inflammatory, angiogenic, and antimicrobial effects of the extracts were examined by flow cytometry, real-time quantitative polymerase chain reaction (RT-qPCR), enzyme-linked immunosorbent assay (ELISA), and well diffusion assays, respectively. Moreover, the antioxidant activity and phenolic and lipid components of H. petaloides were determined. The hexane extract showed the highest cytotoxic activity (IC50 = 26.48 ± 0.02 μg/mL) against A549 cells, while water and methanol extracts exhibited the highest cytotoxicity (IC50 = 83.18 ± 0.05 μg/mL and IC50 = 90.95 ± 0.05 μg/mL, respectively) against PC-3 cells. The hexane extract killed A549 cells via apoptosis. The methanol extract, at the IC50 level, was the most effective in decreasing both tumor necrosis factor-α (TNF-α) and vascular endothelial growth factor (VEGF) release. In antioxidant activity tests performed with 5 different methods, the methanol extract had higher antioxidant activity than the others, followed by 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical (IC50 = 82.61 ± 0.90 μg/mL) and 2,2-azino-bis-3-ethylbenzothiazoline-6-sulfonic acid (ABTS) cation radical removal (IC50 = 55.20 ± 0.65 μg/mL) and CUPRAC-reducing power (IC50 = 76.41 ± 0.73 μg/mL). Among the extracts studied, the hexane extract showed antimicrobial activity against Bacillus cereus, Staphylococcus aureus, Bacillus subtilis, and Micrococcus luteus with different inhibition zones. The major lipid components of H. petaloides analyzed by gas chromatography (GC) and gas chromatography-mass spectrometry (GC/MS) were elaidic acid (38.22%), palmitic acid (30.59%), stearic acid (13.21%), linoleic acid (4.35%), and azelaic acid (4.29%). The phenolic compounds determined by the high-performance liquid chromatography with photodiode-array detection (HPLC-DAD) system were p-hydroxybenzoic acid (7.42 μg/g extract), cinnamic acid (6.83 μg/g extract), gallic acid (5.36 μg/g extract), and protocatechuic acid (1.83 μg/g extract). The results showed that H. petaloides has the potential to be a natural source for the development of novel anticancer and antimicrobial agents as well as a beneficial food supplement for the prevention of cancer.

Design, synthesis and antitumor activity of triphenylphosphonium-linked derivatives of quinazolinone

Cancer is the leading cause of human death. Quinazolinone heterocyclic compounds have a variety of biological activities and have been extensively studied in recent years, especially for their potential anticancer activity. The triphenylphosphonium moiety (TPP+) has become a very important lipophilic cation, especially concerning its application the development of anticancer agents. In this work, we designed and synthesised 24 new TPP+ -conjugated quinazolinone derivatives, which have alkylated TPP+ at the N-3 position and different small group substitutions at the C-6 position, and their antiproliferative activity was evaluated in three cancer cell lines (human alveolar adenocarcinoma cells (A549), human hepatoblastoma cells (HepG2) and human breast cancer cells (MCF-7)) and human normal liver cells (QSG-7701). The cytotoxicity screening results showed that some derivatives exhibited effective inhibitory effects in cancer cells. Among them, the compound 5k–o showed better antiproliferative activity than the positive control drug gefitinib on MCF-7 and A549 cells. The most active compounds being 5o, with IC50 values of 6.56, 14.52 and 7.51 µM in MCF-7 cells, HepG2 cells and A549 cells, respectively. Compound 5o may be a promising compound for cancer treatment worthy of further study.

Exploring the Anticancer Potential of Triazine Derivatives: An Outlook of Designing Strategies, Docking Studies, and Structure‐Activity Relationships (SAR)

AbstractCancer is a disease characterized by uncontrolled cell growth resulting from genetic and epigenetic changes accumulating within a cancer cell population. Despite the milestone discovery of chemotherapeutic drugs against cancer, cancer remains tough to cure. Therefore, cancer has the second‐highest global death rate. There are certain factors such as genetic mutation, cancer cell diversity, metastasis, and resistance, which limit chemotherapy. To combat cancer, it's crucial to find novel therapeutic tactics and produce novel drugs that target cancer cells without affecting healthy cells. Heterocyclic compounds influence certain molecular targets to find novel lead structures can be a noteworthy strategy for the development of potential anticancer agents. Triazine, a low‐cost and widely available heterocyclic scaffold, has piqued researchers’ interest in developing innovative designing strategies. This review presents the advancement of three different isomers of triazines as anticancer agents. The main focus of this review is to provide the advancement of designing strategies, structure‐activity relationships, and docking studies of triazine derivatives as anticancer agents the available triazine‐containing drugs, and the status of clinical trials of triazine‐containing drugs were also highlighted. Lastly, we have also concluded the most potent derivatives and their hybridization with another ring to justify the particular anticancer activity.

Unlocking Fungal Potential: The CRISPR-Cas System as a Strategy for Secondary Metabolite Discovery.

Natural products (NPs) are crucial for the development of novel antibiotics, anticancer agents, and immunosuppressants. To highlight the ability of fungi to produce structurally diverse NPs, this article focuses on the impact of genome mining and CRISPR-Cas9 technology in uncovering and manipulating the biosynthetic gene clusters (BGCs) responsible for NP synthesis. The CRISPR-Cas9 system, originally identified as a bacterial adaptive immune mechanism, has been adapted for precise genome editing in fungi, enabling targeted modifications, such as gene deletions, insertions, and transcription modulation, without altering the genomic sequence. This review elaborates on various CRISPR-Cas9 systems used in fungi, notably the Streptococcus pyogenes type II Cas9 system, and explores advancements in different Cas proteins for fungal genome editing. This review discusses the methodologies employed in CRISPR-Cas9 genome editing of fungi, including guide RNA design, delivery methods, and verification of edited strains. The application of CRISPR-Cas9 has led to enhanced production of secondary metabolites in filamentous fungi, showcasing the potential of this system in biotechnology, medical mycology, and plant pathology. Moreover, this article emphasizes the integration of multi-omics data (genomics, transcriptomics, proteomics, and metabolomics) to validate CRISPR-Cas9 editing effects in fungi. This comprehensive approach aids in understanding molecular changes, identifying off-target effects, and optimizing the editing protocols. Statistical and machine learning techniques are also crucial for analyzing multi-omics data, enabling the development of predictive models and identification of key molecular pathways affected by CRISPR-Cas9 editing. In conclusion, CRISPR-Cas9 technology is a powerful tool for exploring fungal NPs with the potential to accelerate the discovery of novel bioactive compounds. The integration of CRISPR-Cas9 with multi-omics approaches significantly enhances our ability to understand and manipulate fungal genomes for the production of valuable secondary metabolites and for promising new applications in medicine and industry.

A novel D-limonene derivative: synthesis, characterization, molecular docking, molecular dynamics and ADMET prediction studies

Synthesis, characterization, and theoretical studies of a novel limonene-bis(isoxazole)-thiazolidinone hybrid, prepared from natural D-limonene in five steps, were conducted. The compounds obtained were successfully identified using HRMS, 1H- and 13C-NMR spectral data. Subsequently, in-silico docking and molecular dynamic simulation studies were performed to predict potential interaction modes between the compounds and the active sites of the target hTopo IIα. Both studies indicated that all molecules exhibited good binding affinity towards the hTopo IIα enzyme, similar to the reference drug etoposide, when placed in the enzyme’s active site. In addition, in silico ADME/Tox studies were carried out to assess the drug-likeness and pharmacokinetic properties of the molecules. The limonene-bis(isoxazole)-thiazolidinone hybrid derivatives may serve as promising lead compounds for the development of new topoisomerase-targeted anticancer agents.

Homology modelling, molecular docking studies and synthesis of aminopyrimidines as inhibitors for deoxynucleoside kinase analogues in cancer chemoprevention

The development of alternative anticancer agents with minimal side effects has become more critical due to the rising recurrence of mammalian malignancies and the severe side effects of chemotherapeutic treatments. Kinases are an essential target for neostatic impact as they play an important role in the modulation of growth factor signalling. Our work aims to screen novel nine-series of thiazole-based aminopyrimidines and sulphaminopyrimidines against the enzymes mitochondrial thymidine kinase 2, deoxyguanosine kinase (2OCP), deoxycytidine kinase (2QRN) and thymidylate kinase (1E2Q) by molecular docking, synthesise and to study their in vitro inhibitory studies. The synthesised compounds were characterised by Infrared, Nuclear magnetic resonance and Mass spectroscopy. In silico studies, compound 4c stands out among the series, with a reported docking score ranging from −6 to −8 Kcal/mol against all the analogue kinases. The in vitro cytotoxicity assay against human small-cell lung carcinoma (A-549) has shown that 5c (IC50 = 53.9 µM) has an excellent cytotoxic effect over 4c (IC50= 68.68 µM). The reason might be the presence of the benzene sulphonamide group, which enhances their anticancer action. To conclude, the compounds 4c and 5c were found to be potent inhibitors of the deoxynucleoside kinases. In vivo studies must further verify these to prove their potent neostatic effect.

Family Malvaceae: a potential source of secondary metabolites with chemopreventive and anticancer activities supported with in silico pharmacokinetic and pharmacodynamic profiles.

Cancer is the second most widespread cause of mortality following cardiovascular disorders, and it imposes a heavy global burden. Nowadays, herbal nutraceutical products with a plethora of bioactive metabolites represent a foundation stone for the development of promising chemopreventive and anticancer agents. Certain members of the family Malvaceae have traditionally been employed to relieve tumors. The literature concerning the chemopreventive and anticancer effects of the plant species along with the isolated cytotoxic phytometabolites was reviewed. Based on the findings, comprehensive computational modelling studies were performed to explore the pharmacokinetic and pharmacodynamic profiles of the reported cytotoxic metabolites to present basis for future plant-based anticancer drug discovery. All the available information about the anticancer research in family Malvaceae and its cytotoxic phytometabolites were retrieved from official sources. Extensive search was carried out using the keywords Malvaceae, cancer, cytotoxicity, mechanism and signalling pathway. Pharmacokinetic study was performed on the cytotoxic metabolites using SWISS ADME model. Acute oral toxicity expressed as median lethal dose (LD50) was predicted using Pro Tox 3.0 web tool. The compounds were docked using AutoDock Vina platform against epidermal growth factor receptor (EGFR kinase enzyme) obtained from the Protein Data Bank. Molecular dynamic simulations and MMGBSA calculations were performed using GROMACS 2024.2 and gmx_MMPBSA tool v1.5.2. One hundred forty-five articles were eligible in the study. Several tested compounds showed safe pharmacokinetic properties. Also, the molecular docking study showed that the bioactive metabolites possessed agreeable binding affinities to EGFR kinase enzyme. Tiliroside (25), boehmenan (30), boehmenan H (31), and isoquercetin (22) elicited the highest binding affinity toward the enzyme with a score of -10.4, -10.4, -10.2 and -10.1Kcal/mol compared to the reference drug erlotinib having a binding score equal to -9Kcal/mol. Additionally, compounds 25 and 31 elicited binding free energies equal to -42.17 and -42.68Kcal/mol, respectively, comparable to erlotinib. Overall, the current study presents helpful insights into the pharmacokinetic and pharmacodynamic properties of the reported cytotoxic metabolites belonging to family Malvaceae members. The molecular docking and dynamic simulations results intensify the roles of secondary metabolites from medicinal plants in fighting cancer.

Combining lavendustin C and 5-arylidenethiazolin-4-one-based pharmacophores toward multitarget anticancer hybrids

Lavendustin C, a natural-product derived anticancer lead compound, was modified at its carboxylic group by esterification or amidation (compounds 6–10) and at its amino group by introducing 5-arylidenethiazolin-4-ones (14a–c to 17a–c, 18a and 18b). Two strategies were used to combine these moieties and to optimize the yield. These new compounds were evaluated for their antiproliferative activities against a panel of nine cancer cell lines. The results clearly show that 5-arylidenethiazolin-4-one moiety contributes substantially to the activity. Also, methyl esters are more potent than amides, while N-ethylamides are the most potent among amides. 14b showed the highest potency against all tested cancer cell lines with IC50 1.4–2.5 µM, while against normal cell line IC50 > 50 µM. It showed arrest of HeLa cells at G0/G1, S phases and reduction of the percent of cells in G2/M. Moreover, 14b triggered death of HeLa cancer cells via apoptosis induction. EGFR inhibitory potency of 14b was found to be comparable to that of erlotinib. Computational docking and in silico pharmacokinetic studies were performed and discussed. In conclusion, 14b might serve as a multitarget lead compound for further development of anticancer agents.

Urea and Thiourea Derivatives of Salinomycin as Agents Targeting Malignant Colon Cancer Cells.

Since it was discovered that a natural polyether ionophore called salinomycin (SAL) selectively inhibits human cancer cells, the scientific world has been paying special attention to this compound. It has been studied for nearly 15 years. Thus, a very interesting research direction is the chemical modification of SAL structure, which could give more biologically active agents. We evaluated the anticancer activity of (thio)urea analogues class of C20-epi-aminosalinomycin (compound 3b). The studies covered the generation of reactive oxygen species (ROS), proapoptotic activity, cytotoxic activity, and lipid peroxidation in vitro. Thioureas 5a‒5d showed antiproliferative activity against selected human colon cancer cell lines greater than that of chemically unmodified SAL, with a 2~10-fold higher potency towards a metastatic variant of colon cancer cells (SW620). Mechanistically, SAL derivatives showed pro-apoptotic activity in primary colon cancer cells and induced the production of reactive oxygen species (ROS) in these cells. In SW620 cells, SAL derivatives increased lipid peroxidation with a weak effect on apoptosis and low ROS formation with cytotoxic effects followed by cytostatic ones, suggesting different modes of action of the compounds against primary and metastatic colon cancer cells. The results of this study suggested that urea and thiourea derivatives of SAL provide promising leads for the rational development of new anticancer active agents.

Hiding in plain sight: Optimizing topoisomerase IIα inhibitors into Hsp90β selective binders

Due to their impact on several oncogenic client proteins, the Hsp90 family of chaperones has been widely studied for the development of potential anticancer agents. Although several Hsp90 inhibitors have entered clinical trials, most were unsuccessful because they induced a heat shock response (HSR). This issue can be circumvented by using isoform-selective inhibitors, but the high similarity in the ATP-binding sites between the isoforms presents a challenge. Given that Hsp90 shares a conserved Bergerat fold with bacterial DNA gyrase B and human topoisomerase IIα, we repurposed our ATP-competitive inhibitors of these two proteins for Hsp90 inhibition. We virtually screened a library of in-house inhibitors and identified eleven hits for evaluation of Hsp90 binding. Among these, compound 11 displayed low micromolar affinity for Hsp90 and demonstrated a 12-fold selectivity for Hsp90β over its closest isoform, Hsp90α. Out of 29 prepared analogs, 16 showed a preference for Hsp90β over Hsp90α. Furthermore, eleven of these compounds inhibited the growth of several cancer cell lines in vitro. Notably, compound 24e reduced intracellular levels of Hsp90 client proteins in MCF-7 cells, leading to cell cycle arrest in the G0/G1 phase without inducing HSR. This inhibitor exhibited at least a 27-fold preference for Hsp90β and was selective against topoisomerase IIα, a panel of 22 representative protein kinases, and proved to be non-toxic in a zebrafish larvae toxicology model. Finally, molecular modeling, corroborated by STD NMR studies, and the binding of 24e to the S52A mutant of Hsp90α confirmed that the serine to alanine switch drives the selectivity between the two cytoplasmic isoforms.

Ruthenium complexes with abiraterone acetate as antiproliferative agents

This study is dedicated to the development of multimodal anticancer agents. We have obtained ruthenium complexes conjugated with the steroid-type antitumor drug abiraterone acetate in order to take advantage of the dual antitumor properties of both ruthenium and abiraterone. The compounds exhibit good antiproliferative activity against cancer cells, with selectivity over primary fibroblasts. Real-time cell analysis revealed that compound dichlorido(η6-p-cymene)(abiraterone acetate)ruthenium(II) had pronounced antiproliferation activity compared to abiraterone acetate. Flow cytometric studies on the mechanism of cell death have revealed that the most active compound induces apoptosis more effectively than abiraterone acetate. Our findings demonstrate the potential of this novel dual-action compound as promising candidates for further development as anticancer agents.

Synthesis, Antimicrobial - Cytotoxic Evaluation, and Molecular Docking Studies of Quinolin-2-one Hydrazones Containing Nitrophenyl or Isonicotinoyl/Nicotinoyl Moiety.

By applying the hybrid molecular strategy, in this study, we reported the synthesis of fifteen quinolin-2-one hydrazones containing nitrophenyl or nicotinonyl/isonicotinoyl moiety, followed by in vitro and in silico evaluations of their potential antimicrobial and anticancer activities. In vitro antimicrobial evaluation of the target compounds on seven pathogenic strains, applying the broth microdilution method, revealed that compound 4a demonstrated the most potential antifungal activity against C. albicans (MIC 512 μg mL-1) and C. krusei (MIC 128 μg mL-1). In vitro cytotoxic evaluation of the target compounds on three human cancer cell lines, employing the MTT method, suggested that compound 5c exhibited the most potential cytotoxicities against HepG2 (IC50 10.19 μM), A549 (IC50 20.43 μM), and MDA-MB-231 (IC50 16.82 μM) cells. Additionally, molecular docking studies were performed to investigate the binding characteristics of compounds 4a and 5c with fungal lanosterol 14α-demethylase and human topoisomerase I-II, respectively, thereby contributing to the elucidation of their in vitro antifungal and cytotoxic properties. Furthermore, compounds 4a and 5c, via SwissADME prediction, could exhibit favorable physicochemical and pharmacokinetic properties. In conclusion, this study provides valuable insights into the potential of quinolin-2-one hydrazones as promising candidates for the development of novel antimicrobial and anticancer agents in the future.

Synthesis, Molecular Docking, and Anticancer Screening of Ester-Based Thiazole Derivatives.

This study investigates the potential of five compounds as novel anticancer agents. We examined their efficacy, mechanisms of action, and impact on various cancer cell lines, through a comprehensive set of experiments. Notably, compound 3e demonstrated superior activity compared to the positive control cisplatin, with a GI50 value of 6.3±0.7 μM against the breast cancer cell line (MCF-7). Compound 3b also displayed remarkable growth inhibition, yielding GI50 values of 8.7±0.2 μM (MCF-7) and 8.9±0.5 μM against the colon cancer cell line (HCT-116). Cell count experiments further confirmed the potent inhibitory effects of compounds 3e, 3b, and 3c on MCF-7 and HCT-116 cell growth. Compound 3e demonstrated a reduction of 55-60 % at GI50 and complete inhibition (100 %) at 2x GI50. Compound 3b exhibited 50-55 % reduction (GI50) and 90-95 % inhibition (2x GI50) in HCT-116 cells. Compound 3c displayed 75-80 % inhibition (2x GI50) and 35-40 % inhibition (GI50) in HCT-116 cells. In-depth mechanistic investigations unveiled valuable insights into the mode of action of compound 3e. The cell-cycle assay demonstrated G2/M phase arrest, DNA damage, and caspase-mediated apoptosis in both MCF-7 and HCT-116 cells. Caspase activation indicated a significant increase in apoptosis following exposure to compound 3e. Furthermore, compound 3e induced reactive oxygen species (ROS) production, influencing HCT-116 and MCF-7 cells differently. Elevated ROS production in HCT-116 cells and distinct effects in MCF-7 cells contribute to a deeper understanding of the cytotoxic mechanisms of compound 3e. Overall, these findings highlight the potential of the investigated compounds, particularly compound 3e, as effective inducers of apoptosis in cancer cells. Mechanistic insights into cell cycle arrest, caspase-mediated apoptosis, and ROS modulation provide a comprehensive understanding of their cytotoxic effects. This study offers significant contribution to the development of promising anticancer agents and their therapeutic applications.

Thymol-1,2,3-triazole derivatives: Network pharmacology, molecular simulations and synthesis targeting breast cancer

Cancer prevention has become a major focus of public health in the 21st century. Despite advancements in treatment, tackling cancer remains a significant challenge due to the different types of cancer. Breast cancer stands out as the leading cause of cancer-related deaths, highlighting its significant impact on female health worldwide. Monoterpenes, exemplified by thymol, exhibit notable potential in cancer treatment, owing to their pharmacological properties and mechanisms of action. Concurrently, 1,2,3-triazoles have garnered attention as promising entities for the development of anticancer agents, showcasing their efficacy and relevance in oncology research. This study describes the synthesis and characterization of a novel library of 1,2,3-triazole derivatives tethered to p-methoxythymol, a natural product. High-resolution mass spectrometry (HRMS) definitively confirmed the structures of the synthesized compounds, which were further elucidated by detailed analysis of their ¹H- and ¹³CNMR spectra. To predict the suitable target, network pharmacology was applied to the synthesized thymol derivatives, resulting in the identification of phosphatidylinositol-3-kinase (PIK3CA) as a key target. Furthermore, these thymol derivatives were screened for ADMET and molecular docking against the phosphatidylinositol-3-kinase (PIK3CA) target. Molecular dynamics simulations were conducted for the top two compounds over a duration of 100 ns to assess their stability. The RMSD (Root-Mean-Square Devia­tion) and RMSF (root-mean-square fluctuation) values for amino acid residues indicated structural integrity and stable protein-ligand interaction. Additionally, all designed compounds displayed favorable physicochemical properties and ADMET profiles, and two compounds, 4b and 4d, were found to be new lead molecules targeting PIK3CA

Deoxybouvardin targets EGFR, MET, and AKT signaling to suppress non-small cell lung cancer cells

Non-small cell lung cancer (NSCLC) remains a significant challenge, as it is one of the leading causes of cancer-related deaths, and the development of resistance to anticancer therapy makes it difficult to treat. In this study, we investigated the anticancer mechanism of deoxybouvardin (DB), a cyclic hexapeptide, in gefitinib (GEF)-sensitive and -resistant NSCLC HCC827 cells. DB inhibited the viability and growth of HCC827 cells in a concentration- and time-dependent manner. In vitro kinase assay showed DB inhibited epidermal growth factor receptor (EGFR), mesenchymal–epithelial transition (MET), and AKT, and their phosphorylation was suppressed in HCC827 cells treated with DB. A molecular docking model suggested that DB interacts with these kinases in the ATP-binding pockets. DB induces ROS generation and cell cycle arrest. DB treatment of HCC827 cells leads to mitochondrial membrane depolarization. The induction of apoptosis through caspase activation was confirmed by Z-VAD-FMK treatment. Taken together, DB inhibited the growth of both GEF-sensitive and GEF-resistant NSCLC cells by targeting EGFR, MET, and AKT and inducing ROS generation and caspase activation. Further studies on DB can improve the treatment of chemotherapy-resistant NSCLC through the development of effective DB-based anticancer agents.

Synthesis, cytotoxicity and 99mTc-MIBI tumor cell uptake evaluation of 2-phenylbenzothiazole tagged triazole derivatives.

Aim: The extensive utilization of 2-phenylbenzothiazole due to their wide array of biological activities, particularly in cancer therapy, has caused great attention to explore more potent derivatives.Materials & methods: We report the synthesis of 2-phenylbenzothiazole tagged 1,2,3-triaozle (8) through Cu(I)-catalyzed cycloaddition of alkyne side chain with aryl-substituted azides.Results: The in vitro experiments, using MTT and 99mTc-MIBI cell uptake methods, demonstrated the remarkable anticancer activity of these compounds against A549, SKOV3 and MCF7 cell lines.Conclusion: Compounds 8b, 8f and 8i possessed high cytotoxic activity as compared with doxorubicin. Compound 8g has a similar inhibitory effect on the proliferation of breast cancer cells as doxorubicin. In silico study indicated that compound 8 would be a good lead for the development of new potent anticancer agents.

Managing medications for patients with cancer and chronic conditions: It's time for collaboration between primary care and oncology pharmacists.

To provide a rationale for a collaborative care model involving oncology and primary care pharmacists to improve the coordination of care of medications for cancer patients with multiple chronic conditions. A review of selected literature and the authors' own research was used. Studies illustrating the gaps in care for medications and pharmacists' roles in oncology and primary care settings from PubMed were reviewed. There has been a substantial increase in the development and utilization of oral anticancer agents (OAAs). Although OAAs offer convenience and flexibility, they also introduce challenges related to medication adherence, monitoring, and managing side effects. Up to 17.5% of patients experience moderate to severe symptoms from OAAs and about 30% report less than excellent medication adherence. Further, studies showed that 30% to 53% of adult cancer patients have at least one chronic condition that complicates their treatment plan due to the need for medications, increasing the risk of drug interactions, side effects, and non-adherence. The Primary Care Oncology Model (PCOM) incorporates both primary care and oncology pharmacists with comprehensive medication review and patient-reported outcome measure, respectively, to enhance medication appropriateness and effectiveness, and improve overall patient experience. Implementing PCOM may improve the medication management of patients taking OAAs for active cancer treatment and chronic medications for their multiple chronic conditions. This collaborative approach can transform patient care by leveraging the expertise of both primary care and oncology pharmacists.

Pharmacological investigation of new niclosamide-based isatin hybrids as antiproliferative, antioxidant, and apoptosis inducers

A group of Niclosamide-linked isatin hybrids (Xo, X1, and X2) was created and examined using IR, 1HNMR, 13C NMR, and mass spectrometry. These hybrids' cytotoxicity, antioxidant, cell cycle analysis, and apoptosis-inducing capabilities were identified. Using the SRB assay, their cytotoxicity against the human HCT-116, MCF-7, and HEPG-2 cancer cell lines, as well as VERO (African Green Monkey Kidney), was evaluated. Compound X1 was the most effective compound. In HCT-116 cells, compound X1 produced cell cycle arrest in the G1 phase, promoted cell death, and induced apoptosis through mitochondrial membrane potential breakdown in comparison to niclosamide and the control. Niclosamide and compound X1 reduced reactive oxygen species generation and modulated the gene expression of BAX, Bcl-2, Bcl-xL, and PAR-4 in comparison to the control. Docking modeling indicated their probable binding modalities with the XIAP BIR2 domain, which selectively binds caspase-3/7, and highlighted their structural drivers of activity for further optimization investigations. Computational in silico modeling of the new hybrids revealed that they presented acceptable physicochemical values as well as drug-like characteristics, which may introduce them as drug-like candidates. The study proved that compound X1 might be a novel candidate for the development of anticancer agents as it presents antiproliferative activity mediated by apoptosis.